The present invention relates to sustained release drug delivery systems and methods for therapeutic use of the sustained release drug delivery systems. In particular, the present invention relates to sustained release drug delivery systems containing a water soluble therapeutic agent and a release modifier to modify the rate of release of the therapeutic agent from the drug delivery system, and methods for making and using such drug delivery systems. The drug delivery systems disclosed herein can be used for example in methods for treating an ocular condition of a patient.
Various therapeutic agents (such as proteins and polynucleotides) have been used to treat an ocular condition. A difficulty with administration of a therapeutic agent to treat an ocular condition includes being able to appropriately deliver the therapeutic agent in proximity to the desired target tissue. For the treatment of a retinal condition such as macular edema or macular degeneration the target tissue can be the retina or the macula. For the treatment of glaucoma the target tissue can be the ciliary body or photoreceptors of the retina. When a therapeutic agent is not delivered in proximity to the target tissue, for example when a topical pharmaceutical (i.e. an eye drop) is administered to the cornea of eye in order to treat a target tissue within the anterior chamber or the posterior chamber, the therapeutic agent can arrive at the target site in a sub-therapeutic amount and with undesirable side effects upon other tissues. Side effects can include undesirable systemic effects which can result when a relatively large amount of the therapeutic agent is administered, so that a therapeutic amount of the therapeutic agent can be present after administration at the target tissue site. Ocular side effects, such as cataract formation and elevated intraocular pressure, can also result when the therapeutic agent is not administered at a location proximate to the target tissue site.
Another difficulty with administration of a therapeutic agent to treat an ocular condition can result from the desirability of maintaining a therapeutically effective amount of the therapeutic agent proximate to the target tissue for a prolonged period of time, such as for several weeks or months. Thus, because topical formulations of therapeutic agents or aqueous injectables thereof typically disperse, diffuse or are degraded to subtherapeutic levels of the therapeutic agent in a matter of minutes or hours, frequent re-dosing is therefore required to treat a chronic ocular condition.
Sustained release drug delivery systems are known. For example U.S. Pat. No. 6,713,081 discloses polyvinyl alcohol intraocular implants. See also U.S. Pat. Nos. 4,521,210; 4,853,224; 4,997,652; 5,164,188; 5,443,505; 5,501,856; 5,766,242; 5,824,072; 5,869,079; 6,074,661; 6,331,313; 6,369,116; and 6,699,493 and U.S. patent publication 20040170665.
Additionally, release of protein or polynucleotide therapeutic agent from a sustained release drug delivery system is known. See e.g. Jackson J. et al., The encapsulation of ribozymes in biodegradable polymeric matrices, Int J of Pharmaceutics 243 (2002) 43-55, discusses sustained release formulations of ribozymes comprising injectable PLA and PLGA microspheres or a polycaprolactone paste. Jackson suggests controlling the release rate by altering the ribozyme loading. Rosa G., et al., A new delivery system for antisense therapy: PLGA microspheres encapsulating oligonucleotide/polyethyleneimine solid complexes, Int J of Pharmaceutics 254 (2003) 89-93, discloses antisense oligonucleotide PLGA microspheres wherein the in vitro release profile can be changed by changing the nitrogen/phosphate ratio of a polyethylenimine used, drug load or the type of PLGA used. Carrasquillo K. et al., Controlled delivery of the anti-VEGF aptamer EYE001 with poly(lactic-co-glycolic)acid microspheres, IOVS January 2003 44(1), discusses anti-VEGF PLGA microspheres. Khan A. et al., Sustained polymeric delivery of gene silencing antisense ODNs, siRNA, DNAzymes and ribozymes: in vitro and in vivo studies, discusses PLGA microspheres of siRNAs, oligonucleotides, ribozymes and DNAzymes, including one or more of these molecules with an attached lipophilic group to change the release rate. Additionally, see also U.S. patent application Ser. Nos. 11/116,698; 11/364,687, and 11/370,301.
A problem with known sustained release drug delivery systems includes burst release of the therapeutic agent from the drug delivery system. A burst release occurs when more than about 30% of the therapeutic agent contained by the drug delivery system is released from the drug delivery system within about 48 hours after in vivo or in vitro placement (by injection or implantation) of the drug delivery system. Burst release can be a particular problem with water soluble drugs which have a propensity to quickly enter solution in an aqueous physiological environment. A water-soluble therapeutic agent (a therapeutic agent can be referred to synonymously as a drug) is defined as a drug of which 10 mg or more can enter solution in one ml of water at room temperature (20 degrees C.). A slightly or sparingly soluble drug has the property that only from 1 mg to 10 mg of the drug can form a solution in one ml of water at room temperature. A poorly soluble drug has the property that only less than 1 mg of the drug can form a solution in one ml of water at room temperature. Water soluble drugs can include proteins and polynucleotides. Sirna-027, is a highly water-soluble duplex siRNA that can form aqueous solutions of up to 500 mg/mL. A protein can be defined as a polypeptide which comprises two or more amino acid resides and a polynucleotide can be defined as a compound which comprises two or more nucleotides.
It is known to use a release modifier in a drug delivery system so as to modify the rate at which a therapeutic agent is released from the drug delivery system. See eg U.S. Pat. No. 7,048,946.
Aliphatic Alcohols
Aliphatic alcohols (also known synonymously as fatty alcohols or as long chain alcohols or as long chain fatty alcohols) are predominately straight chain organic molecules with an even number of carbon atoms derived from natural fats and oils. Aliphatic alcohols can be converted to or derived from fatty acids and fatty aldehydes. It is known to use the smaller aliphatic alcohols as additives in cosmetics and food, and as industrial solvents. Some larger aliphatic alcohols have been used as biofuels.
Due to their amphipathic nature, aliphatic alcohols can behave as nonionic surfactants and find use as emulsifiers, emollients and thickeners in the cosmetics and food industries. Additionally, aliphatic alcohols are a common component of waxes, mostly as esters with fatty acids but also as alcohols themselves.
Natural Fatty alcohols can be derived from natural fats and oils and are high molecular straight chain primary alcohols. They include lauryl (C12), myristyl (C14), Cetyl (or palmitoyl: C16), stearyl (C18), Oleyl (C18, unsaturated), and Linoleyl (C18, polyunsaturated) alcohols. Synthetic fatty alcohols equivalent physically and chemically to natural alcohols can be obtained from oleochemical sources such as coconut and palm kernel oil. Fatty alcohols have been used as emulsifiers and emollients in skin creams, as well as chemical intermediates. An important use of fatty alcohols is as raw material for the production of fatty sulfate salts and alcohol ethoxylates for foaming and cleaning purposes in the detergent industry. Chemical reactions of primary alcohols include esterifications, ethoxylation, sulfation, oxidation and many other reactions. Derivatives of fatty alcohols and their end use applications include nonionic surfactants (ethoxylates and propoxylates); anionic surfactants (alkyl sulfates and alkyl ethoxy sulfates); chemical intermediates and polymerization modifiers (alkyl halides, alkyl mercaptans); quaternary ammonium compounds for detergent sanitisers, softeners for textiles, phase transfer catalyst and biocides; antioxidants for plastics (alkyl thiopropionates and alkyl phosphites); lubricant additives (metallic and thio alkylphosphates); flavor and fragrance (aldehydes and ketones); PVC plasticizers (dialkyl Phthalates, adipates and trimellitates); coatings and inks (acrylate and methacrylate esters), and; water treatment (acrylate and methacrylate esters) Large amount of fatty alcohols are used as special solvents, fillers in plasticizer and insulating materials for the building industry. Fatty alcohols are used as ingredients in the industries of agricultural, foodstuff, metal processing, cosmetics, lube additive, pharmaceutical, rubber, textile, perfume and flavoring as well as synthetic detergent.
Aliphatic alcohols include:
capryl alcohol (1-octanol)—8 carbon atoms
pelargonic alcohol (1-nonanol)—9 carbon atoms
capric alcohol (1-decanol, decyl alcohol)—10 carbon atoms
lauryl alcohol (1-dodecanol)—12 carbon atoms
myristyl alcohol (1-tetradecanol)—14 carbon atoms
cetyl alcohol (1-hexadecanol: C18H34O)—16 carbon atoms and has a molecular weight of 242.45
palmitoleyl alcohol (cis-9-hexadecan-1-ol)—16 carbon atoms, unsaturated, CH3(CH2)5CH═CH(CH2)8OH
stearyl alcohol (1-octadecanol)—18 carbon atoms
isostearyl alcohol (16-methylheptadecan-1-ol)—18 carbon atoms, branched, (CH3)2CH—(CH2)15OH
elaidyl alcohol (9E-octadecen-1-ol)—18 carbon atoms, unsaturated, CH3(CH2)7CH═CH(CH2)8OH
oleyl alcohol (cis-9-octadecen-1-ol)—18 carbon atoms, unsaturated
linoleyl alcohol (9Z,12Z-octadecadien-1-ol)—18 carbon atoms, polyunsaturated
elaidolinoleyl alcohol (9E,12E-octadecadien-1-ol)—18 carbon atoms, polyunsaturated
linolenyl alcohol (9Z,12Z,15Z-octadecatrien-1-ol)—18 carbon atoms, polyunsaturated
elaidolinolenyl alcohol (9E,12E,15-E-octadecatrien-1-ol)—18 carbon atoms, polyunsaturated
ricinoleyl alcohol (12-hydroxy-9-octadecen-1-ol)—18 carbon atoms, unsaturated, diol, CH3(CH2)5CH(OH)CH2CH═CH(CH2)8OH
arachidyl alcohol (1-eicosanol)—20 carbon atoms
behenyl alcohol (1-docosanol)—22 carbon atoms
erucyl alcohol (cis-13-docosen-1-ol)—22 carbon atoms, unsaturated, CH3(CH2)7CH═CH(CH2)12OH
lignoceryl alcohol (1-tetracosanol)—24 carbon atoms
ceryl alcohol (1-hexacosanol)—26 carbon atoms
montanyl alcohol, cluytyl alcohol (1-octacosanol)—28 carbon atoms
myricyl alcohol, melissyl alcohol (1-triacontanol)—30 carbon atoms, and;
geddyl alcohol (1-tetratriacontanol)—34 carbon atoms.
Behenyl alcohol, lignoceryl alcohol, ceryl alcohol, 1-heptacosanol, montanyl alcohol, 1-nonacosanol, myricyl alcohol, 1-dotriacontanol, and geddyl alcohol are together classified as policosanol, with montanyl alcohol and myricyl alcohol being the most abundant.
1-eicosanol (arachidyl alcohol) has the formula CH3(CH2)18CH2OH and a molecular weight of 298.55. Synonyms are 1-Icosanol; Icosan-1-ol; Icosanol; arachidic alcohol; eicosyl alcohol; 1-prydroxyeicosane, and; eicosanol-(1). It is a white solid with a melting point of 64-66° C.
What is needed therefore is a sustained release drug delivery system for a water soluble therapeutic agent from which drug delivery system the therapeutic agent can be released without a burst effect.